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PURPOSE We report findings on quality of life (QoL) in the RESPECT trial, which compared adjuvant trastuzumab monotherapy with trastuzumab plus chemotherapy in older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). PATIENTS AND METHODS Patients age 70-80 years with human epidermal growth factor receptor 2-positive surgically treated breast cancer were randomly assigned to receive trastuzumab (T) or trastuzumab plus chemotherapy (T + C). QoL was assessed using the Functional Assessment of Cancer Therapy-General (FACT-G), Philadelphia Geriatric Center Morale Scale, Hospital Anxiety and Depression Scale, Patient Neurotoxicity Questionnaire, and Tokyo Metropolitan Institute of Gerontology Index of Competence at baseline and after 2, 12, and 36 months. Comparisons were based on individual changes from baseline and were performed by Fisher’s test or mixed-model repeated-measures. RESULTS Among 275 patients in the parent study, 231 (84%) (average age: 74 years) were included in the analysis. At 2, 12, and 36 months, 198, 177, and 178 patients completed surveys, and the mean FACT-G scores at each survey point were 78.9, 80.4, 82.7, and 79.1 in group T and 79.5, 74.5, 78.4, and 78.5 in group T + C. Compared with group T + C, the proportion of patients showing QoL deterioration (≥ 5 points decrease from baseline in FACT-G) was significantly lower at 2 months (31% v 48%; P = .016) and 12 months (19% v 38%; P = .009). In group T, the Hospital Anxiety and Depression Scale score ( P = .003) and the proportion of severe sensory peripheral neuropathy ( P = .001) were significantly lower at 2 months, and Philadelphia Geriatric Center Morale Scale and Tokyo Metropolitan Institute of Gerontology Index of Competence scores were significantly higher ( P = .024, .042) at 12 months. At 36 months, there were no significant differences in any QoL items. CONCLUSION Detrimental effects of adjuvant chemotherapy on global QoL, morale, and activity capacity lasted for at least 12 months but were not observed at 36 months.

Background As Asians are more vulnerable to febrile neutropenia (FN) than Caucasians, evaluations of FN incidence and risk factors in Asians are important for the appropriate use of primary pegfilgrastim (PEG-G). Patients and methods Japanese breast cancer patients receiving standard adjuvant chemotherapies were prospectively enrolled in multicenter institutions from August 2015 to July 2017. FN was evaluated from 2 treatment policies: true FN (T-FN): ≥37.5 °C, grade 4 neutropenia, mandatory hospital visit (visiting); surrogate FN (S-FN): ≥37.5 °C, oral antibiotic, no mandatory visit (non-visiting). PEG-G was used at the physicians’ discretion. The primary endpoint was FN incidence during all cycles. Multivariate logistic regression analysis was performed to identify T-FN risk factors. Results Of 1005 enrolled patients, 980 women treated with FEC, E(A)C, and TC were analyzed. The FN incidence proportions in all patients were 22.5%, 27.5%, and 33.9% for FEC, E(A)C, and TC, respectively. Those of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5% with more frequent primary PEG-G usage. The relative dose intensity (RDI) of the 3 regimens was ≥0.85 in both groups. In the analysis of risk factors, TC (odds ratio = 2.67), age ≥ 65 years (2.24), and pretreatment absolute neutrophil count (ANC)/1000 μl (0.8) remained significant. Conclusions FN incidences were above 20% in the 3 regimens, with TC showing the highest. RDI was maintained at a high level in both visiting and non-visiting groups. Patient-related risk factors were age and pretreatment ANC., Highlights • This study compared febrile neutropenia (FN) incidences of 3 breast cancer regimens. • FN incidences were >20% in the 3 regimens (FEC, E(A)C; TC); TC showed the highest. • The relative dose intensities in visiting and non-visiting groups were at high level. • Age and pretreatment absolute neutrophil count were found as significant FN factors.

Objective This study examined the pharmacokinetics, safety and anti-tumor activity of docetaxel at a dose of 100 mg/m2 in Japanese patients with advanced or recurrent breast cancer. Methods Japanese patients with advanced or recurrent breast cancer received docetaxel at a dose of 100 mg/m2 intravenously every three weeks. The pharmacokinetics were assessed during the first cycle. The patients were allowed to receive supportive care drugs based on the indications and dosages in Japan. Results Six eligible patients aged 39-65 years old and 27 treatment cycles were analyzed. All patients experienced one or more adverse events (AEs). The common AEs were neutropenia, thrombocytopenia, alopecia, rash, diarrhea, neuropathy (sensory), fatigue, nausea, fever, hypoalbuminemia, alanine transaminase (ALT) increased, constipation, and taste alteration. Grade 3 or 4 AEs included neutropenia, leukopenia, anemia, lymphopenia, decreased appetite, γ-glutamyl transpeptidase (GTP) increased, aspartate transaminase (AST) increased, ALT increased, hypertension and cellulitis which were all reversible. There were no cases of febrile neutropenia, serious AEs or deaths. The median number of cycles was six. Dose reductions were not observed and most cycles were administered at their intended doses. No complete response and three partial responses were observed in four assessable patients with evaluable lesions. The maximum concentration and area under the blood concentration-time curve were 3,417.5 ng/mL and 4.35 μg・hr/mL (mean), respectively. Conclusion Docetaxel at a dose of 100 mg/m2 was tolerable with acceptable safety profiles and effective for Japanese patients with advanced or recurrent breast cancer with appropriate supportive therapies, and pharmacokinetic (PK) profiles which corresponded approximately with the findings of previous clinical studies.

Background Chemotherapy-induced peripheral neuropathy is commonly observed in patients treated with nanoparticle albumin–bound paclitaxel (nab-PTX). We conducted a multicenter randomized controlled study to evaluate the optimal dose of nab-PTX. Methods We compared three different doses of q3w nab-PTX (Standard: 260 mg/m2 [SD260] vs Medium: 220 mg/m2 [MD220] vs Low: 180 mg/m2 [LD180]) in patients with HER2-negative metastatic breast cancer (MBC). Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses were estimated using the logistic regression model. The optimal dose was selected in two steps. Initially, if the hazard ratio (HR) for PFS was 1.33, the inferior dose was excluded, and we proceeded with the non-inferior dose. Then, if the estimated incidence rate of grade 3/4 neurotoxicity exceeded 10%, that dose was also excluded. Results One hundred forty-one patients were randomly assigned to SD260 (n = 47), MD220 (n = 46), and LD180 (n = 48) groups, and their median PFS was 6.66, 7.34, and 6.82 months, respectively. The HRs were 0.73 (95% confidence interval [CI]: 0.42–1.28) in MD220 vs SD260, 0.77 (95% CI 0.47–1.28) in LD180 vs SD260, and 0.96 (95% CI 0.56–1.66) in LD180 vs MD220. SD260 was inferior to MD220 and was excluded. The estimated incidence rate of grade 3/4 neurotoxicity was 29.5% in SD260, 14.0% in MD220, and 5.9% in LD180. The final selected dose was LD180. Conclusions Intravenous administration of low-dose nab-PTX at 180 mg/m2 q3w may be the optimal therapy with meaningful efficacy and favorable toxicity in patients with MBC., Highlights • Nab-Paclitaxel at 260 mg/m2 is used to treat metastatic breast cancer (MBC). • Nab-Paclitaxel frequently causes severe neuropathy or myalgia. • A reduced nab-paclitaxel dose of 180 mg/m2 q3w was effective and had less toxicities. • Therapeutic indices of reduced doses were increased compared to the standard dose.

To report our findings on quality of life (QoL) in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC). Patients with HER2-negative MBC were randomly assigned to three different doses of q3w nab-PTX (SD 260 mg/m2 vs. MD: 220 mg/m2 vs. LD 180 mg/m2). QoL was assessed at baseline and during the second, fourth and sixth courses of treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Cancer Fatigue Scale (CFS) and EuroQol 5-Dimension (EQ-5D). Comparisons were performed with mixed-model repeated measures (MMRM). A total of 141 patients were enrolled in the parent study, and 136 (96%) (44, 45 and 47 in the SD, MD, and LD groups) were included in the analysis. MMRM analysis showed that the difference from the baseline FACT-Taxane trial outcome index at MD and LD were significantly higher than that at SD (MD vs. SD P

Introduction Patients with residual disease usually have a poor prognosis after neoadjuvant chemotherapy for breast cancer. The aim of this study was to explore therapeutic targets and potential additional adjuvant treatments for patients with residual disease after standard neoadjuvant chemotherapy. Patients and Methods We retrieved publicly available complementary DNA microarray data from 399 human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer samples from patients who underwent standard neoadjuvant chemotherapy. We analyzed the messenger RNA (mRNA) expression levels of key breast cancer markers and therapeutic target genes according to residual cancer burden (RCB) classification: RCB-0/I, RCB-II, and RCB-III. Results Among hormone receptor–positive samples, there were more luminal A tumors by PAM50 (Prediction Analysis of Microarray 50 [Prosigna], aka Prosigna Breast Cancer Prognostic Gene Signature Assay) in RCB-III than in RCB-0/I and RCB-II (P < .01). The mRNA expressions of ESR1 and PGR were significantly higher, and that of MKI67 was lower in RCB-II and RCB-III than in RCB-0/I. The mRNA expression of cyclin D1 was up-regulated in RCB-III and that of CDKN2A was down-regulated in RCB-III (P = .027 and < .01). Among triple-negative (TN) samples, RCB-III had higher clinical stage and more lymph node–positive samples than RCB-0/1 and RCB-II (P < .01). In both subtypes, VEGF-C expression was significantly higher in RCB-III than in RCB-0/I and RCB-II. Conclusion In hormone receptor–positive breast cancer, biological features such as luminal A were associated with RCB; this trend was not observed in TN breast cancer. Further, some targeted therapies should be tested as new strategies after standard neoadjuvant chemotherapy in future clinical trials.

OBJECTIVE: Nab-paclitaxel (nab-PTX) has superior efficacy compared to conventional paclitaxel in metastatic breast cancer (MBC), but chemotherapy-induced peripheral neuropathy (CIPN) is more frequent with nab-PTX. In a single arm phase 2 trial (CA002-0LD), low dose nab-PTX (175 mg/m2) every 3 weeks (q3w) resulted in a good objective response rate (39.5%) without CIPN of grade 3 or higher. Therefore, we conducted a randomized controlled study to evaluate the optimal dose of nab-PTX by comparing a low dose (LD) and a medium dose (MD) to the standard dose (SD). Here, we evaluate the patients-reported outcomes (PROs) and health-related quality of life (HRQoL) in the ABROAD study. PATIENTS AND METHODS: Three different doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2) were administered in patients with HER2-negative metastatic breast cancer. The primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates with the three doses were estimated by logistic regression. The optimal dose was selected by 2-step selection. First, if the hazard ratio (HR) for PFS was 1.33, the inferior dose was dropped. Then, a dose with an estimated incidence of grade 3/4 neurotoxicity >10% was also dropped. PROs and HRQoL were assessed as secondary endpoints at baseline, and during the 2nd, 4th and 6th courses of protocol treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Patient Neurotoxicity Questionnaire (PNQ), Cancer Fatigue Scale (CFS) and EuroQol 5 Dimension (EQ-5D). The primary outcome for PROs and HRQoL was the FACT-Taxane trial outcome index (TOI), and inter-group comparison was performed using a mixed effect model for repeated measures (MMRM). This trial was registered with the University Hospital Medical Information Network (UMIN), Japan (protocol ID C000012429). RESULTS: A total of 141 patients were randomly assigned to SD (n=47), MD (n=46) or LD (n=48) nab-PTX. PFS analysis showed that LD nab-PTX at 180 mg/m2/3 weeks was the optimal dose with good clinical efficacy and tolerability for patients with MBC (reported by Hara at ASCO2019). Longitudinal analysis (MMRM) showed that the difference from the baseline FACT-Taxane TOI score at MD and LD were significantly better than that at SD (MD vs. SD p CONCLUSION: Our results show that low dose nab-PTX at 180 mg/m2/3 weeks could be an optimal dose for PFS and from the perspectives of PROs and HRQoL. Citation Format: Hiroaki Kato, Fumikata Hara, Masahiro Kitada, Masato Takahashi, Yuichiro Kikawa Yuichiro Kikawa, Eiko Sakata, Yoichi Naito, Yoshie Hasegawa, Tsuyoshi Saito, Tsutomu Iwasa, Junji Tsurutani, Naruto Taira, Tsutomu Takashima, Kosuke Kashiwabara, Tomohiko Aihara Tomohiko Aihara, Hirofumi Mukai. Patient-reported outcomes in a randomized, optimal dose finding, phase II study of triweekly nab-paclitaxel in patients with metastatic breast cancer (the ABROAD study) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-04.

Background In hormone receptor (HR)-positive / human epidermal growth factor receptor 2 (HER2)-negative breast cancers, high Ki-67 predicts poor prognosis. Recently, it has been reported that among breast cancers with high Ki-67, low Ki-67 after short-term preoperative hormone therapy (post Ki-67) might predict favorable prognosis compared to high post Ki-67 (SABCS 2017). However, the differences in gene expression profiling of breast cancers between high and low post Ki-67 among high Ki-67 before treatment are unclear. Therefore, this study aimed to clarify genetic differences in two groups and to explore novel therapeutic targets for the poor prognostic group after the treatment. Methods Seventy-seven patients with primary HR-positive / HER2-negative breast cancer who received an aromatase inhibitor for 2 weeks [NCBI Gene Expression Omnibus repository GSE80077:19 cases, GSE20181:58 cases] were enrolled in this study. Forty-five patients with high pre Ki-67 among them were stratified into two groups, high (H→H) and low (H→L) post Ki-67 after short-term preoperative hormone therapy. We compared gene expression profiling in two groups about the followings. 1) 3 genes (ESR1, PGR and ERBB2) related to classical clinical treatment strategy of breast cancer, immune- and inflammatory-related genes 2) 178 pathways (gene set analysis) 3) 41 genes that are targeted by FDA-approved drugs or have been investigated with clinical trials as molecular target agents for various malignant tumors including breast cancer Results 1) TNF that is inflammatory-related gene were significantly overexpressed in H→L group (P=0.021). However, 3 genes related to clinical treatment of breast cancer and immune-related genes expression had no significant difference between two groups. 2) 5 gene sets (Tryptophan metabolism, Propanoate metabolism, beta-Alanine metabolism, SNARE interactions in vesicular transport and Nucleotide excision repair) were significantly upregulated in H→L group. (P ≤ 0.005) 3) 5 targeted genes (PARP, BRCA2, FLT4, CDK6 and PDCD1LG2) were significantly overexpressed in H→H group (P ≤ 0.05). Conclusions There were different gene expression and biological processes in two groups stratified by post-Ki67. In the future, it is necessary to seek new therapeutic strategies for poor prognostic group with high post-Ki67 in considerations of these differences. Citation Format: Yukiko Kajiwara, Takayuki Iwamoto, Yusuke Otani, Miwa Fujihara, Yoko Suzuki, Minami Hatono, Takahiro Tsukioki, Kengo Kawada, Mariko Kochi, Hirokuni Ikeda, Tadahiko Shien, Naruto Taira, Hiroyoshi Doihara. Gene expression profiling of breast cancers between high and low Ki-67 after short-term preoperative hormone therapy among hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancers with high Ki-67 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-13-04.

Background: Currently, treatment for older breast cancer patients is largely based on data derived from trials enrolling younger patients; thus, the standard of care for older breast cancer patients remains controversial. Aim: To investigate the clinicopathological characteristics, treatments, and prognosis in older stage II and III breast cancer patients using data from the Japanese Breast Cancer Registry (JBCR). Methods: We reviewed data from the JBCR, a nationwide registry of newly diagnosed and operated primary breast cancer patients in Japan. To clarify those characteristics, we compared clinicopathological characteristics, treatments, and prognosis among three groups: older group, patients aged ≥75 years; young-old group, patients aged 65–74 years; post-menopause group, patients aged 55–64 years. Results: In total, we reviewed 56,093 cases of stage II/III breast cancer diagnosed between 2004 and 2011 (older: n=12,727; young-old: n=17,860; post-menopause: n=25,506). The estrogen receptor (ER) positivity rate was higher (older vs. young-old vs. post-menopause: 73.3% vs. 72.0% vs. 68.0%) and HER2 positivity rate was lower in the older group than in the other two groups (12.9% vs. 16.8% vs. 23.6%) (p The following table shows the rate of administration of adjuvant systemic therapy according to the ER and HER2 status. Age (years)≥7565–7455–64p-valueER+Chemotherapy10.042.562.9 Nearly half of the older patients (48.3%) who received chemotherapy received either cyclophosphamide-methotrexate-fluorouracil or oral fluorouracil. As for hormone therapy, tamoxifen was used more frequently in the older group than in the young-old and post-menopause groups (16.5% vs. 8.6% vs. 7.2%). The following table shows the results of the 5-year overall survival (OS) and breast cancer-specific survival (BCSS) analyses: Conclusions: Chemotherapy was less common in older patients, especially patients with HER2+ or triple negative breast cancer, resulting in worse BCSS. As older patients tend to have several comorbidities, comprehensive geriatric assessment might be helpful in determining systemic therapies for older patients. Age (years)≥7565–7455–64p-valueER+OS/BCSS (%)84.1/94.592.5/96.093.2/94.9 Citation Format: Akimitsu Yamada, Masataka Sawaki, Hiraku Kumamaru, Hiroaki Miyata, Kanako Nakayama, Chikako Shimizu, Mika Miyashita, Naoko Honma, Itaru Endo, Naruto Taira, Shigehira Saji. Systemic therapy for and prognosis of older stage II and III breast cancer patients: Evaluation of data from the Japanese breast cancer registry [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-06.

Background: The randomized controlled trial (RCT) is accepted as the standard clinical trial to decide a standard therapy, but it remains unclear whether or not elderly patients benefit as much as other patients from participation in an RCT. In the RESPECT study (NCT01104935), the relative value of trastuzumab (H) monotherapy as an adjuvant treatment was compared in an RCT with the standard combination treatment with chemotherapy (H+CT) in patients over 70 years old with HER2-positive invasive breast cancer (BC) who received curative surgery. This cohort study was aimed at comparing prognoses between RCT participants (RCT group) and non-participants (Cohort group). Methods: Patients were divided into RCT participants, and those who did not agree to participate in the RCT despite meeting the eligibility criteria and receiving the explanation given by the investigator. In the RCT group patients were randomized to H or H+CT; in the Cohort group treatment was selected for each patient based on the discretion of the treating physician and the patient's wishes without intervention. Treatment categories were divided into three groups: (1) trastuzumab monotherapy group (cH group), (2) trastuzumab plus chemotherapy group (cH+CT group), and (3) those who received either no therapy at all, or any other anticancer therapies without H (cOther group). The primary endpoint was disease-free survival (DFS). Secondary endpoints were overall survival (OS), relapse-free survival, safety, health-related quality of life (HRQOL) and comprehensive geriatric assessment. Results: A total of 275 patients in the RCT group and 123 patients in the Cohort group, in total 398 patients, were enrolled in this study between October 2009 and October 2014. The median age was 74.0 years in the RCT group, 74.5 years in the Cohort group and the median follow-up time was 4.1 years and 3.2 years, respectively. Patients were classified as Stage I: 41.8%, 42.5%; IIA: 41.5 %, 40.8%; IIB: 13.5%, 13.3%; and IIIA: 1.5%. 3.3%, respectively (P = 0.51), there were no significant differences between the two groups. Treatment categories in the Cohort group were: (1) cH group; 43% (n = 52), (2) cH+CT group; 30% (n = 36), cOther group; 27% (n = 32). The planned analysis showed that DFS at 3 years was 91.4% in the RCT group vs 89.3% in the Cohort group (adjusted hazard ratio (HR) = 1.30; 95%CI, 0.72-2.35, P = 0.38). In patients in the cH+CT, cH and cOther group, DFS at 3 years was 92.3%, 89.2% and 82.5%, respectively. DFS in patients in the cH+CT and the cH group was significantly better than that of the cOther group (adjusted HR = 3.79; 95%CI = 1.35-10.64, P = 0.01). DFS in the cH group showed a better tendency compared with cOther (adjusted HR = 2.59; 95%CI, 0.87-7.73, P = 0.08). The incidence of grade 3/4 non-hematological adverse events in the RCT group was relatively higher compared with the Cohort group (18.5% vs 10.8 %, P = 0.05). Conclusion: The prognosis did not vary between the RCT and Cohort groups. H-containing regimens are often chosen for elderly patients with HER2-positive breast cancer. The prognosis of patients who received any H-containing regimen, even H monotherapy, was better than those who were not treated with H. Citation Format: Shinichi Baba, Masataka Sawaki, Yukari Uemura, Tsuyoshi Saito, Kokoro Kobayashi, Hiroaki Kawashima, Michiko Tsuneizumi, Noriko Sagawa, Hiroko Bando, Masato Takahashi, Miki Yamaguchi, Tsutomu Takashima, Takahiro Nakayama, Masahiro Kashiwaba, Toshiro Mizuno, Yutaka Yamamoto, Naruto Taira, Hiroji Iwata, Tatsuya Toyama, Koichiro Tsugawa, Yasuo Ohashi, Hirofumi Mukai. A cohort study to evaluate the efficacy and safety of postoperative adjuvant therapy in HER2-positive elderly breast cancer patients (RESPECT-cohort study) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-14-02.

Background: The standard chemotherapy treatment strategy for patients with advanced/metastatic breast cancer (ABC) is the continuation of the same drug until tumor progression. However, despite continued antitumor effects, continuation of a drug often becomes difficult because of cumulative adverse events, such as peripheral neuropathy. Methods: This multicenter, randomized, Phase II study in patients with estrogen receptorpositive (ER+) human epidermal growth factor receptor 2-negative (HER2−) ABC aimed to compare 2 treatment strategies following induction therapy with 4-6 cycles of the combined use of weekly paclitaxel (wPTX) and bevacizumab (BV). Patients in Arm A continued with wPTX+BV, whereas patients in Arm B were switched from wPTX to maintenance endocrine therapy (endocrine+BV) until disease progression, followed by wPTX+BV re-induction. The primary endpoint was time to failure of strategy (TFS), defined as the time from randomization to a qualifying event (addition of a new agent not in the primary regimen, progressive disease during or after planned therapy, or death). Secondary endpoints were overall survival (OS), progression-free survival, safety, and quality of life (QoL). Sequential plasma and serum biomarkers were analyzed for predicting/monitoring the response. Result: Of 160 patients enrolled to receive induction therapy with wPTX+BV, 125 patients responded to treatment (complete response [CR], partial response [PR], or stable disease) and were randomized to either of the 2 treatment arms. Median follow-up was 21.3 months. Aromatase inhibitor (AI), fulvestrant, or AI with a luteinizing hormonereleasing hormone (LH-RH) analogue was used as maintenance endocrine therapy. The primary endpoint of TFS was 8.87 months (95% CI: 5.68-13.80) in the wPTX+BV continued group (Arm A) and 16.82 months (95% CI: 12.88-18.99) in the maintenance endocrine+BV group (Arm B) (hazard ratio [HR], 0.51; p Conclusion: This is the first study showing the benefit of maintenance endocrine therapy in patients with ER+ HER2− advanced breast cancer who responded to a fixed dose of chemotherapy. (UMIN: UMIN000012179; ClinicalTrials.gov: NCT01989780) Funding: Chugai Pharmaceutical CO., LTD. Citation Format: Shigehira Saji, Masahiro Kitada, Toshimi Takano, Masahiro Takada, Tohru Ohtake, Tatsuya Toyama, Yuichiro Kikawa, Yoshie Hasegawa, Tomomi Fujisawa, Masahiro Kashiwaba, Takanori Ishida, Rikiya Nakamura, Yutaka Yamamoto, Uhi Toh, Hiroji Iwata, Norikazu Masuda, Naruto Taira, Satoshi Morita, Shinji Ohno, Masakazu Toi. A randomized, multicenter, phase II study evaluating the efficacy of interventional maintenance endocrine therapy with bevacizumab following fixed cycles of bevacizumab plus paclitaxel in advanced/metastatic ER-positive HER2-negative breast cancer: JBCRG-M04 BOOSTER trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-01.

Purpose To gauge the effects of treatment practices on prognosis for all older patients with HER2-positive breast cancer, particularly to determine whether adjuvant trastuzumab alone can offer benefit over no adjuvant therapy. This report accompanies the RESPECT study, a randomized-controlled trial (RCT) comparing trastuzumab monotherapy with trastuzumab-plus-chemotherapy for early HER2-positive breast cancer.Patients and methods Patients who declined the RCT were treated based on the physician’s discretion. We studied the (1) trastuzumab-plus-chemotherapy group, (2) trastuzumab-monotherapy group, and (3) non-trastuzumab group (no therapy or anticancer therapy without trastuzumab). The primary endpoint was disease-free survival (DFS), which was compared using the propensity-score method.Results We enrolled 398 eligible patients, aged over 70 years, with HER2-positive invasive breast cancer, of whom 275 (69%) were in the RCT, and 123 (31%) were in this cohort group. The median age was 74.5 years. Among cohort group treatment categories were as follows: (1) trastuzumab-plus-chemotherapy group (n = 36, 30%), (2) trastuzumab-monotherapy group (n = 52, 43%), and (3) non-trastuzumab group (n = 32, 27%). A total of 73% of patients received trastuzumab-containing regimens, with or without chemotherapy. The 3-year DFS was 92.3% in the trastuzumab-plus-chemotherapy group, 89.2% in the trastuzumab-monotherapy group, and 82.5% in the non-trastuzumab group. DFS in the non-trastuzumab group was lower than in the trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted HR: 3.29; 95% CI: 1.15–9.39; P = 0.026). The relapse-free survival in the non-trastuzumab group was lower than in the trastuzumab-plus-chemotherapy and trastuzumab monotherapy groups (propensity-adjusted HR = 7.80; 95% CI: 2.32–26.2, P < 0.0001). Chemotherapy with trastuzumab or trastuzumab monotherapy did not affect health-related quality of life (HRQoL) at 36 months.Conclusions Trastuzumab-treated patients had better prognoses than patients not treated with trastuzumab without deterioration of HRQoL. Thus, trastuzumab monotherapy can be considered for patients who reject chemotherapy.Trial registration number The protocol was registered on the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID: UMIN 000028476).

OBJECTIVE: The effect of trastuzumab(Tmab) or chemotherapy on cognitive function has not been fully understood, especially in elderly breast cancer patients. The RESPECT trial compared 1-year(yr) Tmab monotherapy with Tmab plus standard chemotherapy as adjuvant therapy in elderly patients with HER2-positive breast cancer. The primary objective was to verify the noninferiority of 1-yr Tmab monotherapy compared to Tmab plus chemotherapy in terms of disease-free survival, and the planned analysis showed that the difference of restricted mean survival time between two groups at 3 yrs was 0.45 months (Sawaki at ASCO2018). The goal of this report was to assess the impact of the treatment groups on longitudinal cognitive function. PATIENTS AND METHODS: The study was performed with patients from 99 hospitals in Japan. Elderly women with HER2-positive, stage I-IIIA invasive breast cancer surgery treated with clear resection margins were randomly assigned to either receive 1-yr Tmab or 1-yr Tmab plus standard chemotherapy. 15 institutions participated in the cognitive sub-study. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) at baseline and at 1 and 3 yrs after treatment. The primary outcome was the amount of change in the MMSE score from the baseline. A linear mixed-effects model was used for comparisons of change in the MMSE score between groups, controlling for time and baseline score. Secondary outcomes were the proportion of both suspected mild dementia (MMSE≤27) and dementia (MMSE≤23) at each time point. RESULTS: Between October 2009 and October 2014, 275 patients were enrolled in the RESPECT trial, and 57 patients were enrolled in the cognitive function sub-study with 2 patients subsequently excluded. The 55-patient sub-study comprised 29 patients assigned to the Tmab monotherapy group and 26 patients assigned to the Tmab plus chemotherapy group. Primary analysis revealed that change in the MMSE score was not significantly different between the two groups (difference −0.6 at 1 yr and −0.9 at 3 yrs; p=0.136), whereas the baseline score was the only significant factor that had an effect on the amount of change in the MMSE score (p CONCLUSION: Postoperative chemotherapy for elderly breast cancer patients was considered to have little effect on the onset of dementia during the follow-up period of 3 yrs. Further long-term observation is necessary to obtain a significant conclusion. Citation Format: Takahashi M, Sawaki M, Hagiwara Y, Uemura Y, Kawahara T, Shimozuma K, Ohashi Y, Saito T, Baba S, Kobayashi K, Mukai H, Taira N. Analysis of cognitive function in elderly HER2-positive breast cancer patients receiving either trastuzumab monotherapy or trastuzumab plus chemotherapy as a postoperative adjuvant treatment: A cognitive function sub-study of a randomized, open-label, phase 3 clinical trial (RESPECT trial) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-21.

Background: Overall survival (OS) is the established endpoint to evaluate the effects of drug treatment in comparative clinical trials of metastatic breast cancer. But assessing OS requires long follow-up periods and large sample size, which raise costs and create long delays in the drug approval process. Progression-free survival (PFS) or time to progression (TTP) is considered as a surrogate for OS and is often used as an alternative to OS. In some cancers the two endpoints are highly correlated, but in others they are not. Furthermore, the effect of breast cancer (BC) subtypes on the surrogacy of PFS/TTP for OS has not been completely defined. Method: A systematic literature review of randomized control trials was conducted to identify studies that reported both the hazard ratio (HR) of PFS/TTP and OS for BC subtypes {i.e. estrogen receptor (ER) positive, HER2 positive, and triple negative (TN)}. The correlation between the HR of PFS/TTP and OS was evaluated using weighted Spearman's rank correlation. Results: A total of 49 trials (34 phase III trials and 15 phase II trials) were selected for analysis. Among these trials, there were 8 comparison trials between one chemotherapy and another chemotherapy regimen, 18 comparison trials between chemotherapy and chemotherapy plus molecularly-targeted therapy, 9 comparison trials between one endocrine therapy and another endocrine therapy, and 5 comparison trials between endocrine therapy and endocrine therapy plus molecularly-targeted therapy. There were 17 trials reporting the HR of PFS/TTP and OS for ER positive, 16 trials for HER2 positive, and 9 trials for TN BC. Weighted Spearman's rank correlation revealed that coefficient between the HR of PFS/TTP and OS was 0.721(p Conclusion: There was a strong correlation between the HR of PFS/TTP and OS for ER positive BC, and a weak correlation between the HR of PFS/TTP and OS for HER2 positive and TN BC. The validity of using PFS/TTP as an OS surrogate marker was shown for metastatic BC, especially for ER positive BC. Citation Format: Tsukioki T, Taira N, Sakamaki K, Suzuki Y, Kajiwara Y, Hatono M, Takahashi Y, Kawata K, Kochi M, Iwamoto T, Ikeda H, Shien T, Doihara H. Progression-free survival or time to progression in comparative clinical trials of metastatic breast cancer as a potential surrogate for overall survival: A systematic review of 49 trials focusing on breast cancer subtype [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-19.

OBJECTIVE: The RESPECT trial compared 1-year trastuzumab monotherapy with trastuzumab plus standard chemotherapy as a postoperative adjuvant therapy in HER2-positive elderly breast cancer patients. Primary objective of this study was to verify the noninferiority of 1-year trastuzumab monotherapy to trastuzumab plus chemotherapy in terms of disease free survival, and the planned analysis showed that the difference of restricted mean survival time between two groups at 3 years was 0.45 months (reported by Sawaki at ASCO2018). This report assesses the patients-reported outcomes and health-related quality of life (HRQoL). PATIENTS AND METHODS: The study was done at 99 hospitals in Japan. Elderly women (70 to 80 years old) with HER2-positive, stageI-IIIA invasive breast cancer treated by surgery with clear resection margins were randomly assigned to receive either 1-year trastuzumab or 1-year trastuzumab plus standard chemotherapy, stratified by age, hormone-receptor status, pathological lymph node metastasis and institution. Patients completed questionnaires at baseline, 2 months, 1year, and 3 years after protocol treatment started. The primary outcome was global HRQoL assessed using Functional Assessment of Cancer Therapy-General (FACT-G) total score, and secondary outcomes were chemotherapy-induced peripheral neuropathy (CIPN), instrumental activities of daily living (IADL), anxiety, depression, and subjective happiness. We did the analyses by intention to treat, including patients who completed questionnaires at baseline before start of protocol treatment, and 5point or more change is meaningful in FACT-G total score. This study is registered with ClinicalTrials.gov, NCT01104935. RESULTS: Between Oct 2009 and Oct 2014, 275 patients were enrolled in the study, of whom 9 patients were excluded: 135 assigned to trastuzumab monotherapy and 131 assigned to trastuzumab plus chemotherapy. We detected significant difference between treatment groups for: clinically meaningful HRQoL deterioration rate at 2 months (31% for trastuzumab monotherapy vs 48% for trastuzumab plus chemotherapy; p=0.016) and at 1year (19% vs 38%; p=0.009), clinically meaningful HRQoL improvement rate at 2 months (38% for trastuzumab monotherapy vs 15% for trastuzumab plus chemotherapy; p CONCLUSION: Given the small advantage of adjuvant trastuzumab plus chemotherapy compared to trastuzumab monotherapy for elderly HER-2 positive breast cancer women, decisions about treatment should be informed by the risk for adverse health effects associated with chemotherapy. Citation Format: Kobayashi K, Taira N, Sawaki M, Sagawa N, Baba S, Saito T, Kawahara T, Hagiwara Y, Uemura Y, Shimozuma K, Ohashi Y, Mukai H. Patient-reported outcomes with trastuzumab monotherapy versus trastuzumab plus standard chemotherapy as a postoperative adjuvant therapy in HER2-positive elderly breast cancer patients (RESPECT): A randomized, open-label, phase 3 clinical trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-13-02.

Background:It is unclear how to define responsiveness to endocrine therapy (ET) during the clinical course of advanced breast cancer (ABC), especially in evaluation of the effect of sequential ET. Objective:The goal of the study was to evaluate the efficacy of second line treatment of physician's choice (2nd-line TPC) for estrogen receptor-positive (ER+) and HER2-negative postmenopausal ABC with very low or low sensitivity to initial ET. Methods:A multicenter prospective observational cohort study was performed for 2nd-line TPCs. ABC with low sensitivity to initial ET was defined as recurrence within 5 years (yrs) during adjuvant ET or progression within 9 months (mo.) of initial ET. Similarly, ABC with very low sensitivity to initial ET was defined as recurrence within 2 yrs during adjuvant ET or progression within 3 mo. of initial ET. The expected clinical benefit rate (CBR: defined as patients who achieved CR, PR or SD for 24 weeks) was 50%. The null hypothesis of a CBR of 30% was tested with a one-sided α of 5%. 90% confidence intervals (CIs) were calculated for hypothesis tests. Results: A total of 56 patients (pts) were enrolled, but 7 were ineligible and one discontinued before starting the protocol treatment. The median age was 66 yrs (range: 41-88) and the median BMI was 23.4 kg/m2 (16.4-31.9). All pts were ER+ and 80% were PgR+. Most of pts had a baseline PS of 0 or 1, 90% had invasive ductal carcinoma, and 10% had invasive lobular carcinoma. Postoperative recurrence was detected in 84% and these pts had a median duration of adjuvant ET of 30.5 mo. (5.3-58.9). De novo stage IV ABC was present in 16%, with a median duration of first-line ET of 5 mo. (2.3-10.8). Adjuvant chemotherapy including anthracycline- and/or a taxane-containing regimen was administered in 58% (29/49). As adjuvant ET before initial recurrence, 34 pts received non-steroidal aromatase inhibitors (AIs) (88.0%), 1 received a steroidal AI (2.3%), and 3 received a selective estrogen receptor modulator (SERM). As first line ET in de novo stage IV, 7 pts (14%) were treated with AIs or a SERM (1 case). 2nd-line TPCs were also used, with 40 pts receiving fulvestrant (82%), 5 receiving SERMs (10%), 3 receiving a mTOR inhibitor plus a steroidal AI (6%), and one patient receiving an AI alone. The overall CBR was 44.9% (90% CI: 34.6-57.6, p=0.009), and CBR was similar across following subgroups (PgR+: n=39, 51.3%, 90% CI: 39.6-65.2, p=0.0016; very low sensitivity group: n=17, 58.8%, 90% CI: 42.0-78.8, p=0.003; non-visceral metastases: n=25, 40%, 90% CI; 34.1-65.9, p=0.0175). However, there were not statistically significant CBR in PgR- (n=10, 20.0%, 90% CI; 8.73-50.7, p=0.617), fulvestrant subgroup (n=40, 40.0 %, 90% CI; 29.2-54.2, p=0.063), low sensitive group (n=32, 37.5%, 90% CI; 26.0-53.6, p=0.1326), and visceral metastases (n=24, 48%, 90%CI; 28.2-60.3 p=0.072). The median PFS was 7.1 mo. (95% CI: 5.6-10.6). Conclusion:This study shows that 2nd line ETs was effective and might be a valid option in the sequence of treatments for postmenopausal women with ABC with low sensitivity to initial ET. It was suggested that PgR and visceral metastasis were significant predictive factors for CBR. Citation Format: Araki K, Fujisawa T, Sakamaki K, Kikawa Y, Iwamoto T, Sangai T, Shien T, Takao S, Nishimura R, Takahashi M, Aihara T, Mukai H, Taira N. Sequential second line endocrine therapy is still an effective strategy for postmenopausal ER+ and HER2- advanced breast cancer with low sensitivity to initial endocrine therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-09.

Purpose Patients with breast cancer may develop cognitive impairment as a result of hormone therapy and aging. This study aimed to describe older patients’ experience of cognitive impairment related to hormone therapy for breast cancer. Methods A qualitative and descriptive design was used. Semi-structured interviews were conducted for 11 patients to ask about their experience in daily life related to their cognitive impairment. Study participants were evaluated by cancer-specific geriatric assessment. Inductive content analysis was conducted using interview records. Results Three themes emerged from the patients’ narrative data: recognizing of cognitive impairments, impacts on mental health, and coping with cognitive impairments. Recognizing of cognitive function consisted of two categories: perception of cognitive changes and acknowledging their cognitive function status through interacting with others. Impacts on mental health consisted of six categories: decreased motivation for social activities, upset by perception of cognitive decline, concerns about impacts of cognitive impairment on treatment of breast cancer, concerns about care burden of their family, concerns about progressing of cognitive impairments, and feeling secure that their cognitive impairment is not unusual. Coping with cognitive impairments consisted of two categories: coping with problems related to cognitive impairment and trying to maintain and improve cognitive function. Conclusion Medical professionals should perform a comprehensive evaluation of older patients receiving hormone therapy for breast cancer.

This study aimed at investigating the real-world prognostic impact of systemic treatment in older patients with stage II/III breast cancer (BC)., This retrospective cohort study included patients with stage II/III primary BC, aged ≥55 years, and registered in the Japanese Breast Cancer Registry from 2004 to 2011. The clinicopathological characteristics, treatments, and prognosis of patients aged ≥75 years (older) were compared to those of younger patients., In total, 56,093 patients (12,727, ≥75 years; 17,860, 65-74 years; 25,506, 55-64 years) were enrolled. In the older group, 9.2% with a luminal (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-), 32.9% with a triple-negative (TN, HR-/HER2-), and 27.4% with a HER2-positive (any-HR/HER2+) receptor were administered chemotherapy. In those with luminal cancer, the 5-year breast cancer-specific survival (BCSS) was approximately 95% in all age groups. Meanwhile, among those with TN and HER2-positive BC, the older group had a poorer BCSS. The 5-year overall survival (OS) was also poorer in the older group across all subtypes. Among older patients matched using clinicopathological factors, chemotherapy use was associated with improved OS in the luminal and HER2-positive subtypes., Chemotherapy use was lower among older patients with stage II/III breast cancer. Those with TN and HER2-positive BC had a lower BCSS than their younger counterparts. Chemotherapy may be beneficial in improving the OS in older patients with luminal and HER2-positive BCs. Treatment for older patients should be individualized, based on tumor-related factors, quality of life, and the patient's health status.

To investigate whether postoperative adjuvant trastuzumab plus chemotherapy negatively affected cognitive functioning during the post-chemotherapy period compared with trastuzumab monotherapy in older patients with HER2-positive breast cancer. In the randomized RESPECT trial, women aged between 70 and 80 years with HER2-positive, stage I to IIIA invasive breast cancer who underwent curative operation were randomly assigned to receive either 1-year trastuzumab monotherapy or 1-year trastuzumab plus chemotherapy. Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) test at enrollment and 1 and 3 years after initiation of the protocol treatment. The primary outcome was change in the MMSE total score from baseline. Secondary outcomes included prevalence of suspected mild cognitive impairment (MMSE total score

Introduction The previous randomized phase 3 trial (SELECT BC) showed that S-1 as a first-line chemotherapy for metastatic breast cancer (MBC) is non-inferior to taxane with respect to overall survival. This study aimed to identify the usefulness of metabolism-related genes as predictive biomarkers for the response to S-1 compared with taxane using tumor tissue samples from the previous trial. Patients and Methods In this SELECT BC-EURECA study, 147 patients with human epidermal growth factor 2 (HER2)-negative MBC who received either S-1 or taxane were evaluated. Formalin-fixed paraffin-embedded specimens were collected, and 14 genes involved in the pyrimidine metabolic pathway, estrogen receptor, progesterone receptor, HER2, Ki67, and beta-tubulin were measured using reverse transcription polymerase chain reaction in microdissected tumor specimens. The expression of each gene was categorized as low, intermediate, and high by tertile values. Results Interaction tests to identify biomarkers for the response to S-1 compared with taxane, revealed the following as the top 3 biomarkers: RRM1 (P value = 0.24), GGH (P value = 0.25), and MTHFR (P value = 0.28). In the S-1 group, lower GGH and higher MTHFR expression were significantly correlated with better time to treatment failure. In the taxane group, there was no gene that was identified as a significant indicator of treatment failure. Conclusion This biomarker analysis from SELECT BC did not identify any predictive biomarkers for the response to S-1 compared with taxane. Future studies with larger sample size and information on not only mRNA, but also protein and DNA for broad functional analyses are needed.

Minimal data are available to support the clinical management of older breast cancer patients. Consequently, the standard of care remains unclear. Our aim was to clarify the clinicopathological characteristics, practical treatments, and prognosis of older Japanese breast cancer patients and discuss clinical issues. We reviewed 132,240 cases, diagnosed between 2004 and 2011, from the Japanese Breast Cancer Registry. Focusing on older patients, we compared data among three age groups: 75 years and over (n = 27,385), 65–74 years (n = 43,839), and 55–64 years (n = 61,016). Data revealed the proportions of mucinous and apocrine carcinoma were higher in older patients, and they more frequently had clinical stage II and III cancer. Their ER-positive rates were higher, in contrast to the lower HER2-positive, breast-conserving surgery (BCS), post-BCS irradiation, and adjuvant chemotherapy rates. Almost half of the older patients who underwent chemotherapy received CMF or oral 5FU, during hormone therapy, Tamoxifen was administered more frequently. The overall survival rate decreased with age, but the breast cancer-specific survival (BCSS) at 5 years remained similar. The rate of other cause of death in the oldest group was about a half, and more than double that in those aged 55–64 years. We showed clinical data of older breast cancer patients in Japan. Their disease was more advanced at the time of diagnosis, post-BCS irradiation and primary systemic chemotherapy were omitted more frequently, and overall, BCSS was similar among age categories, although the rate of other causes of death was higher.

PURPOSE Adjuvant trastuzumab monotherapy has not been compared with trastuzumab + chemotherapy. We investigated the relative value of trastuzumab monotherapy for older patients with breast cancer. METHODS This study was an open-label, randomized controlled study with a treatment selection design in which a noninferiority criterion was predefined. Patients aged 70-80 years with surgically treated human epidermal growth factor receptor 2–positive invasive breast cancer received trastuzumab monotherapy or trastuzumab + chemotherapy. The primary end point was disease-free survival (DFS) with assessment of prespecified hazard ratio (HR), relapse-free survival (RFS), adverse events (AEs), health-related quality of life (HRQoL), and restricted mean survival time (RMST). RESULTS The study involved 275 patients (mean age, 73.5 years) who were followed up for a mean of 4.1 years (range, 0.3-8.0 years). The percentages of patients by cancer stage were as follows: I (pT > 0.5 cm), 43.6%; IIA, 41.7%; IIB, 13.5%; and IIIA, 1.1%. Three-year DFS was 89.5% with trastuzumab monotherapy versus 93.8% with trastuzumab + chemotherapy (HR, 1.36; 95% CI, 0.72 to 2.58; P = .51). At 3 years, RMST differed by −0.39 months between arms (95% CI, −1.71 to 0.93; P = .56). Three-year RFS was 92.4% with trastuzumab monotherapy versus 95.3% with trastuzumab + chemotherapy (HR, 1.33; 95% CI, 0.63 to 2.79; P = .53). Common AEs were anorexia (7.4% v 44.3%; P < .0001) and alopecia (2.2% v 71.7%; P < .0001), and grade 3/4 nonhematologic AEs occurred in 11.9% versus 29.8% ( P = .0003) for trastuzumab monotherapy versus trastuzumab + chemotherapy, respectively. Clinically meaningful HRQoL deterioration rate showed significant differences at 2 months (31% for trastuzumab monotherapy v 48% for trastuzumab + chemotherapy; P = .016) and at 1 year (19% v 38%; P = .009). CONCLUSION The primary objective of noninferiority for trastuzumab monotherapy was not met. However, the observed loss of survival without chemotherapy was < 1 month at 3 years. Therefore, and in light of the lower toxicity and more favorable HRQoL profile, trastuzumab monotherapy can be considered an adjuvant therapy option for selected older patients.

Recent genome-wide association studies have shown that many single-nucleotide polymorphisms (SNPs) are associated with breast cancer risk. However, it is often unclear how these SNPs are related to breast cancer. Analysis of associations between SNPs and phenotypes may be important for determining mechanisms of action, including carcinogenesis. In previous case–control studies, we found three SNPs (rs2046210, rs3757318, and rs3573318) associated with breast cancer risk in Japanese women. Among these SNPs, two (rs2046210 and rs3757318) are located at 6q25.1, in proximity to the estrogen receptor 1 gene (ESR1). Using data from these studies, we examined associations between factors related to breast cancer risk, such as height, weight, and breast density, and the three SNPs in cases and controls. We also investigated whether the SNPs correlated with breast cancer features, such as estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor type-2 (HER2) status, and clinical stage. There was a significant difference in mean height between risk and non-risk allele carriers for rs2046210 (156.0 ± 5.8 vs. 154.3 ± 5.5 cm, p = 0.002), and rs3757318 (155.8 ± 5.7 vs. 154.7 ± 5.6 cm, p = 0.035) in cases, but no significant associations between height and these SNPs in controls. There was also a significant difference in breast density between risk and non-risk allele carriers for rs2046210 (p = 0.040) and rs3757318 (p = 0.044) in cases. rs2046210 and rs3757318 risk allele carriers tended to have higher breast density in all subjects and in controls. In cases, rs3757318 risk allele carriers were also significantly more likely to be ER-negative compared to non-risk allele carriers (ER-positive rate: 77% vs. 84%, p = 0.036). SNPs rs2046210 and rs3757318, which are associated with breast cancer risk in Japanese women, were significantly associated with height and high breast density, and this association was particularly strong in those with breast cancer. These findings suggest that SNPs in the ESR1 gene region affect phenotypes such as height and breast density.

Purpose Metformin has been suggested to possibly reduce cancer risk. However, the mechanism underlying the positive effects of metformin on cancer treatment remains unclear. We conducted a prospective study to evaluate the effects of preoperative metformin in patients with early breast cancer. Method We evaluated the effects on immunological factors (TILs, CD4 + , CD8 + , PD-L1, IFNγ and IL-2) by comparing core needle biopsies (CNB) obtained before metformin treatment with surgical specimens. Seventeen patients were enrolled in this prospective study from January to December 2016. We also analyzed 59 patients undergoing surgery during the same period to reveal the correlation of immune factors between CNB and surgical specimen. Result There was a moderate correlation between CNB and surgical specimens on TILs and CD8 + lymphocyte. (TILs Rs = 0.63, CD4 + Rs = 0.224, CD8 + Rs = 0.42) In the metformin group, TILs increases were confirmed in five (29%) patients, while a decrease was confirmed in two (12%). The expressions of CD4 + and CD8 + by TILs were increased in 41% and 18% of surgical specimens, respectively. However, TILs number (p = 0.0554), CD4+ (p = 0.0613) and CD8 + (p = 0.0646) expressions did not significantly increased. Furthermore, IFNγ expression appeared to be increased in response to metformin (p = 0.08). Conclusion Preoperative metformin tends to increase TILs, as well as the numbers of CD4 and CD8 positive lymphocytes, and IFNγ levels. Metformin might improve immune function and have a possibility of chemo-sensitivity and thereby increase the effectiveness of immunotherapy, based on the results of this preliminary study.

Purpose Second-line endocrine therapy (ET) for estrogen receptor (ER)-positive and human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC) is offered based on the response to first-line ET. However, no clinical trials have evaluated the efficacy and safety of secondary ETs in patients with poor responses to initial ET. This study evaluated the efficacy of second-line ET in ER-positive and HER2-negative postmenopausal MBC patients with low or very low sensitivity to initial ET. Methods This multicenter prospective observational cohort study evaluated the response of 49 patients to second-line ETs in postmenopausal MBC patients with low or very low sensitivity to initial ET. The primary endpoint was the clinical benefit rate (CBR) for 24 weeks. Results Of the 49 patients assessed, 40 (82%) received fulvestrant in the second line, 5 (10%) received selective estrogen receptor modulators, 3 (6%) received aromatase inhibitors (AIs) alone, and 1 received everolimus with a steroidal AI. The overall CBR was 44.9% [90% confidence interval (CI): 34.6–57.6, p = 0.009]; CBR demonstrated similar significance across the progesterone receptor-positive (n = 39, 51.3%, 90% CI: 39.6–65.2, p = 0.002), very low sensitivity (n = 17, 58.8%, 90% CI: 42.0–78.8, p = 0.003), and non-visceral metastases (n = 25, 48.0%, 90% CI: 34.1–65.9, p = 0.018) groups. The median progression-free survival was 7.1 months (95% CI: 5.6–10.6). Conclusion Second-line ET might be a viable treatment option for postmenopausal patients with MBC with low and very low sensitivity to initial ET. Future studies based on larger and independent cohorts are needed to validate these findings.

The PRECIOUS study (UMIN000018202) is being conducted as a multicenter, randomized, open-label Phase III study to determine if retreatment with pertuzumab is more effective than conventional treatment in HER2-positive locally advanced (LA)/metastatic breast cancer (MBC) patients previously treated with pertuzumab, trastuzumab and chemotherapy. Patients are randomized 1:1 into chemotherapy plus trastuzumab with or without pertuzumab groups. The latest regimen before enrollment did not include pertuzumab, and the number of previous chemotherapy regimens for LA/MBC did not exceed three. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include independent reviewer-assessed progression-free survival, progression-free survival in patients treated with trastuzumab emtansine as the latest regimen, response rate, response duration, overall survival, safety and health-related quality of life. Target accrual is 370 patients, allowing the observation of 325 events, yielding an 80% power for detection of a hazard ratio of 0.739 with a one-sided 5% level of significance.

Objective The aim of this study was to investigate the impact of adverse events (AEs) on health utility and health-related quality of life (HRQOL) in patients with metastatic breast cancer undergoing first-line chemotherapy. Methods We analyzed the data from the SELECT BC study, a multicenter, open-label, randomized, phase III study conducted in Japan, which compared first-line S-1 with taxane therapies. Heath utility and HRQOL were assessed using the EQ-5D-3L and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at baseline and 3, 6, and 12 months after treatment initiation. Health utility was calculated based on societal preferences, and AEs were reported at each cycle of the study treatment. Linear marginal mean models were used to quantify the impact of the last AEs (with 10 or more incidences) observed before HRQOL assessment on health utility and HRQOL. Results Analysis included 380 patients and 12 (of 15) AEs. Grade 1 nausea and oral mucositis, grade 1 and 2 edema, and grade 2 fatigue, motor and sensory neuropathy, and myalgia were significantly associated with disutility, measured using the EQ-5D-3L. Grade 1 oral mucositis, grade 1 and 2 fatigue, and grade 2 sensory neuropathy were significantly associated with impaired global health status in the EORTC QLQ-C30. AEs associated with decrements in the five functioning scales included fatigue, oral mucositis, nausea, edema, motor and sensory neuropathy, and myalgia. Conclusions We reported disutilities caused by AEs in patients with metastatic breast cancer under chemotherapy. These findings can be applied to future model-based cost-effectiveness analyses. Trial Registration Number C000000416. Electronic supplementary material The online version of this article (doi:10.1007/s40273-017-0580-7) contains supplementary material, which is available to authorized users.

The present study evaluated whether morphological-measured stromal and intra-tumour tumour-infiltrating lymphocytes (TILs) levels were associated with gene expression profiles, and whether TILs-associated genomic signature (GS) could be used to predict clinical outcomes and response to therapies in several breast cancer subtypes. We retrospectively evaluated haematoxylin eosin (HE)-TILs levels and gene expression profiling data from 40 patients with primary breast cancer and extracted the 22 overexpressed genes in cases with high TILs scores as the TILs-GS. The TILs-GS were compared with breast cancer subtype and were evaluated predictive values for prognosis and response to therapies. Higher TILs-GS expressions were observed for triple-negative and human epidermal growth factor receptor 2 (HER2) positive (+) breast cancers, compared to the luminal types (P

Objective We investigated the quantification of the response shift–adjusted treatment effect on quality-of-life (QOL) data in a randomized controlled trial of taxane versus S-1 for patients with metastatic breast cancer (SELECT-BC). Methods This study was a secondary data analysis of a previously published trial. The response shift–adjusted treatment effect on health-related QOL (HRQOL) data measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was estimated using structural equation modeling techniques in addition to quantifying the “true” treatment effect. Measurement invariances in the values of the common factor loadings, intercepts, and residual variances between before treatment and at the 3-, 6-, and 12-month visits were considered the response shift effects. Results In the taxane group, we observed positive recalibration effects for role functioning and positive reprioritization and negative recalibration effects for emotional functioning. The observed change of −4.56 for role functioning comprised +2.26 response shifts and −6.82 “true” change. The observed change of +9.41 for emotional functioning comprised +12.43 response shifts and −1.17 “true” change. In the S-1 group, we observed positive reprioritization and negative recalibration effects for emotional functioning and positive reprioritization effects for social functioning. The observed change of +10.54 for emotional functioning comprised +10.07 response shifts and +0.47 “true” change. The observed change of +2.43 for social functioning comprised +3.50 response shifts and −1.07 “true” change. Conclusion Detailed analysis of the response shift effects will improve the evaluation reliability of observed HRQOL data during clinical trials.

Gemcitabine (Gem) with paclitaxel (Pac) is used for patients with metastatic breast cancer who require cytoreduction with manageable toxicities. Nanoparticle albumin-bound (nab)-Pac exhibits better efficacy and reduces the risk of hypersensitivity reactions associated with solvent-based Pac. Therefore, Gem plus nab-Pac (GA) therapy may be effective for metastatic breast cancer. The purpose of this study was to determine the maximum tolerated dose for GA therapy.The subjects were patients with metastatic breast cancer with performance status 0 or 1 and normal hepatic, renal and marrow function. Leukopenia, neutropenia or thrombocytopenia of grade 4, neutropenic fever, or non-hematological toxicity of grade 3 or higher during the 1st cycle, and chemotherapy-induced peripheral neurotoxicity of grade 2 or higher at the end of the 1st cycle were defined as dose-limiting toxicities (DLTs). Gem (1250 mg/m(2)) was administered on days 1 and 8. nab-Pac was administered at a starting dose of 180 mg/m(2) (cohort 1) and escalated to 220 mg/m(2) (cohort 2) and 260 mg/m(2) (cohort 3) on day 1 of the 21-day cycle, using a 3 + 3 design.Nine patients (n = 3, 3, and 3 in cohorts 1, 2, and 3, respectively) were included in the study (median age 56 years; range 43-75 years). DLTs did not occur in any cohorts.The initial recommend dose in GA therapy is 1250 mg/m(2) Gem and 260 mg/m(2) nab-Pac. It is well known that nab-Pac has cumulative toxicities, and thus the efficacy and safety of GA therapy require validation in a phase 2 study.

Background: Tumor infiltrating lymphocytes (TIL) in subtypes of breast cancer may provide clinically important information on chemotherapy response and prognosis. However, the standardized methodology for immunohistochemical (IHC)-TIL has not yet been established, reproducible and objective method of evaluation of TIL such as gene expression profiles is warranted. We evaluated whether IHC-TIL level was associated with gene expression profiles and whether such profiles could be used to predict chemotherapy response and prognosis according to subtypes of breast cancers. Methods: To select TIL associated genes, we used 40 samples with both IHC-TIL information and gene expression profiling data. The degree of TIL at the edges of the tumor mass, in the tumor mass, or in the stroma surrounding the expanding mammary ducts packed by carcinoma cells was evaluated as score 0, 1, and 2, when TIL was not unrecognizable (0%), sparse (0 << 50%) and dense (50% ≤), respectively. We selected 22 genes as the TIL-gene signature (GS), by comparing expression profiles between TIL score 2 and 0 tumors. We showed the associations between the TIL-GS levels and subtypes of breast cancers (Estrogen receptor: ER / Human Epidermal growth factor 2: HER2). The chemotherapy sensitivity analysis was performed on cohorts of 625 patients with stage I–III breast cancer who received neo adjuvant chemotherapy (NAC) based on Anthracycline and Taxane containing regimen. Data from 1,586 tumors were used to evaluate the association between distant metastasis free survival (DMFS) and the TIL-GS in a Kaplan-Meier analysis. Results: The TIL-GS for ER negative (-)/HER2- and HER2 positive (+) cases were significantly higher expression level than luminal types (p-value Conclusions: Higher TIL-gene signature of 22 genes appeared to be associated with aggressive subtypes and pCR rate (except luminal-low) of breast cancers. This approach may improve the reproducibility of assessment on tumor TIL level and thus serve the clinical applications for breast cancers. Citation Format: Kochi M, Niikura N, Iwamoto T, Bianchini G, Mizoo T, Nogami T, Shien T, Motoki T, Taira N, Masuda S, Doihara H, Fujiwara T, Tokuda Y, Matsuoka J. Tumor Infiltrating lymphocytes (TIL) related genomic signature associated with chemotherapy response and prognosis in subtypes of breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-14.

Background: There is a high risk of under-reporting subjective toxicities by physicians, even when collected prospectively in clinical trials. It has been recommended to include patient reported measures regarding symptoms in prospective clinical comparative effectiveness trials. However, there have been few reports of agreement in endocrine related symptoms between patient and physician reporting. Patients and Method: The National Surgical Adjuvant Study of Breast Cancer 06 (N-SAS BC 06) is a multicenter, randomized clinical trial of postmenopausal, hormone receptor-positive breast cancer patients, with a two-stage (preoperative and postoperative) enrollment, and intervention. The primary aim was to evaluate the need for adjuvant chemotherapy in the treatment of postmenopausal breast cancer patients who responded to neoadjuvant treatment with Letrozole (LET) for 24-28 weeks. After surgery, responders were randomized into two arms receiving either chemotherapy plus LET, or LET alone. The primary endpoint was disease-free survival, and the secondary endpoints included adverse events, quality of life and health economic evaluation. This study enrolled 497 subjects from the N-SAS BC 06 who were evaluated by Patient Reported Outcomes (PROs). The concordance rate between Clinician Reported Outcomes (CROs) and PROs in their endocrine symptoms during neoadjuvant endocrine therapy was examined. Symptoms were collected prospectively by physicians using the Common Toxicity Criteria for Adverse Events at enrollment, i.e., baseline, and 4 and 16 weeks after starting neoadjuvant LET. Patients also completed the FACT-G (General), B (Breast), ES (Endocrine Symptoms), and HADS. The endocrine symptoms according to the PROs, included nausea, hot flushes, cold sweats, headaches, and HADS-Depression score. In FACT, "Not at all" was used to express the absence of the symptoms, and "A little bit", "Some-what", "Quite a bit", and "Very much" were used to express the presence of symptoms. The HADS-Depression score threshold was 10/11. According to the CROs, grade 0 was defined as the absence of symptoms and grade 1 or more was defined as the presence of symptoms. Cohen's kappa was used to determine the concordance between CROs and PROs. The sensitivity of CROs was also calculated. Results: The calculated point estimates of Cohen's kappa at Weeks 4 and 16 after starting neoadjuvant LET were 0.12 and 0.01 for nausea, 0.16 and 0.18 for hot flushes, 0.12 and 0.09 for cold sweats, 0.03 and 0.02 for headaches, and 0.11 and 0.11 for dysthymia/depression, respectively; the concordance was quite low. The sensitivity of CROs at Weeks 4 and 16 after starting neoadjuvant LET was 0.07 and 0.03 for nausea, 0.16 and 0.17 for hot flushes, 0.1 and 0.08 for cold sweats, 0.03 and 0.03 for headaches, and 0.11 and 0.1 for dysthymia/depression, respectively; the sensitivity was quite low. Conclusion: This study showed that there were big differences between CROs and PROs in endocrine symptoms associated with endocrine therapy for breast cancer and that physicians could not obtain sufficient information on the endocrine symptoms. It is recommended that PROs be used to evaluate adverse events caused by endocrine therapy. Citation Format: Fujisawa T, Iwata H, Sakai T, Nakamura R, Hasegawa Y, Ohtani S, Kashiwaba M, Taira N, Toyama T, Masuda N, Yamamoto Y, Kihara K, Shimozuma K, Ohashi Y, Mukai H. Endocrine-related symptoms during neoadjuvant endocrine therapy for breast cancer: Agreement between patient and physician reporting in a prospective clinical trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-02.

Background: There are few randomized clinical trials examining adjuvant treatment in elderly breast cancer patients. While obtaining informed consent is essential for participation in clinical studies, there is little information on the frequency of agreement to participate among elderly patients. Furthermore, elderly patients might have specific reasons to decline participation. Patients and Method: The National Surgical Adjuvant Study of Breast Cancer 07 (N-SAS BC 07) is a randomized clinical trial in women over 70 years with HER2-positive primary breast cancer. The primary aim was to investigate the benefit of trastuzumab monotherapy compared with the combination of trastuzumab and chemotherapy. Key inclusion criteria were as follows: women between 70 and 80 years old with HER2-positive breast cancer; underwent curative operation; stage I to IIIA; with sufficient organ function. Patients were randomized to receive either trastuzumab plus chemotherapy or trastuzumab monotherapy. The primary endpoint was disease-free survival, and the secondary endpoints were overall survival, relapse-free survival, safety, health-related quality of life, and cost effectiveness (NCT01104935). It was not possible to predict the number of patients who would agree to participate. In order to comprehensively assess the effect of postoperative adjuvant therapy, we evaluated the reasons why eligible patients declined to participate. The patients were registered in a cohort study to prospectively evaluate the subsequent treatment options and prognosis (07-Cohort). This study examined the obtaining of informed consent for N-SAS BC 07 and the reasons for declining participation, and compared the clinicopathological backgrounds between the N-SAS BC 07 and 07-Cohort groups. Results: 398 eligible patients have been recruited. Informed consent to participate in N-SAS BC 07 has been obtained from 275 patients (69%) and 123 patients (31%) who declined to participate in the RCT have been registered in the 07-Cohort. The common reasons to decline participation in the RCT were "cannot choose the treatment option (55%)", "refused chemotherapy (16%)", "wanted chemotherapy (9%)", "anxious about clinical studies (9%)" and "family opposition (8%)". The mean ages of the patients in N-SAS BC 07 and 07-Cohort were 73.9 and 74.6 years old, respectively. There were no differences in stage, surgical procedure, lymph node metastasis, or co-morbidities between the groups. ER-positive rate was higher in 07-Cohort group compared with N-SAS BC 07 group (53% vs. 37%, p=0.017, χ2 test). Conclusion: While we expected the number of registrants to be small, since N-SAS BC 07 investigated whether elderly patients with HER2-positive breast cancer should undergo chemotherapy, almost 70% of the patients accepted informed consent. The most common reason to decline participation in N-SAS BC 07 was "cannot choose the treatment option" and the majority refused chemotherapy. Furthermore, ER-positivity was higher in the 07-Cohort group, which suggested that ER expression in the patients with HER2-positive breast cancer might influence their decision to participate in the study or to choose the treatment option. Citation Format: Sagara Y, Sawaki M, Taira N, Saito T, Kashiwaba M, Iwata H, Kobayashi K, Nakayama T, Bando H, Mizuno T, Yamamoto Y, Tsuneizumi M, Takahashi M, Yamaguchi M, Kawashima H, Takashima T, Uemura Y, Hozumi Y, Sagawa N, Mukai H, Ohashi Y. A randomized clinical trial of postoperative adjuvant therapy for elderly breast cancer patients: Conditions of obtaining informed consent and reasons for declining participation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-18-01.

Background: Health-related quality of life (HRQoL) is one of the important outcomes in cancer control trials and has increasingly become the one of the primary foci. Obtaining informed consent from participants is essential for participation in randomized controlled trials (RCTs), but the participation in these RCTs may directly influence HRQoL, because treatment options are determined according to the allocation schedule. To date, only a few studies have compared HRQoL between clinical trial participants and decliners. Patients and Method: The National Surgical Adjuvant Study of Breast Cancer 07 (N-SAS BC 07) is a randomized controlled trial in women with HER2-positive primary breast cancer who are over 70 years of age. The primary aim was to investigate the benefit of trastuzumab monotherapy compared with combination therapy using trastuzumab and chemotherapy. The study concept and design were published in concept paper (Sawaki M. et al., Jpn J Clin Oncol. 2011). In this study, patients were randomized to receive either trastuzumab plus chemotherapy or trastuzumab monotherapy. The primary endpoint was disease-free survival, and the secondary endpoints were overall survival, relapse-free survival, safety, HRQoL, comprehensive geriatric assessment (CGA) and cost effectiveness (protocol ID; NCT01104935). HRQoL and CGA were assessed at registration (baseline), 2 month, 1 year, and 3 years after the start of protocol treatments using the Functional Assessment of Cancer Therapy-General (FACT-G), Hospital Anxiety and Depression Scale (HADS), EuroQol 5 Dimension (EQ-5D), Tokyo Metropolitan Institute of Gerontology (TMIG) index of competence, and the Philadelphia Geriatric Center (PGC) Morale Scale. The patients who declined to participate in N-SAS BC 07 were registered in a cohort study to prospectively evaluate the subsequent treatment options and prognosis (07-Cohort). The same questionnaire that was used in N-SAS BC 07 was used in 07-Cohort to evaluate HRQoL and CGA at entry. Results: Patients were enrolled from October 2012 to October 2016. During this period, 275 and 123 patients were registered in N-SAS BC 07 and 07-Cohort, respectively. The mean age at entry of the patients in the N-SAS BC 07 and 07-Cohort groups was 73.9 and 74.6 years, respectively. The questionnaire response rates at baseline in the patients in N-SAS BC 07 and 07-Cohort groups were 89% and 82%, respectively. There were no significant differences in FACT-G, HADS, EQ-5D, or TMIG index of competence at baseline between the groups, but the mean (standard deviation) scores of PGC Morale Scale in N-SAS BC 07 and 07-Cohort groups were 10.8 (3.3) and 9.9 (3.7), respectively, with the scores being significantly greater in the N-SAS BC 07 group (p=0.020, t-test). Conclusion: The PGC Morale Scale provides a multidimensional approach to assess the psychological state of older people. This study indicated that participation in the RCT did not affect the baseline QoL of elderly patients but suggested that the baseline QoL of the RCT participants was better than decliners. Citation Format: Saito T, Sawaki M, Hozumi Y, Sagawa N, Iwata H, Kashiwaba M, Kawashima H, Kobayashi K, Taira N, Takashima T, Takahashi M, Tsuneizumi M, Nakayama T, Baba S, Bando H, Mizuno T, Yamaguchi M, Yamamoto Y, Uemura Y, Ohashi Y, Mukai H. A randomized controlled trial of postoperative adjuvant therapy for elderly breast cancer patients: Comparison of health-related quality of life between clinical trial participants and decliners. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-09.

Purpose The Recurrence Score test is validated to predict benefit of adjuvant chemotherapy. TransNEOS, a translational study of New Primary Endocrine-therapy Origination Study (NEOS), evaluated whether Recurrence Score results can predict clinical response to neoadjuvant letrozole. Methods NEOS is a phase 3 clinical trial of hormonal therapy ± adjuvant chemotherapy for postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer, after six months of neoadjuvant letrozole and breast surgery. TransNEOS patients had tumors ≥ 2 cm and archived core-biopsy samples taken before neoadjuvant letrozole and subsequently sent for Recurrence Score testing. The primary endpoint was to evaluate clinical (complete or partial) response to neoadjuvant letrozole for RS

PURPOSE: Glucocorticoids are used to prevent chronic lung allograft dysfunction (CLAD) after lung transplantation (LT). Our study was aimed at assessing the association between the glucocorticoid-induced transcript 1 gene (GLCCI1) variant, which modulates glucocorticoid sensitivity, and the postoperative lung function and development of CLAD after LT. METHODS: A total of 71 recipients of LT were genotyped for the GLCCI1 variant (rs37972) and divided into three groups: the homozygous mutant allele (TT) group, the heterozygous mutant allele (CT) group, and the wild-type allele (CC) group. The results of pulmonary function tests were compared with the postoperative baseline values. RESULTS: The total lung capacity (TLC) in the TT group was significantly lower than that in the CC group at 3 years after LT (P = 0.029). In the recipients of cadaveric LT, the TLC and forced expiratory volume in 1 s in the TT group were significantly lower than those in the CC groups, resulting in a significant worse CLAD-free survival at 3 years after LT (P = 0.016). CONCLUSION: The GLCCI1 variant was associated with a significant decrease of the TLC at 3 years after LT and the development of CLAD at 3 years, especially in patients undergoing cadaveric LT.

Perioperative dose-dense chemotherapy (DDCT) with granulocyte-colony stimulating factor (G-CSF) prophylaxis is a standard treatment for patients with high-risk breast cancer. The approval of this approach in Japan led to the widespread adoption of DDCT, despite limited efficacy and safety data among Japanese patients. We evaluated the efficacy and safety of neoadjuvant DDCT for Japanese patients with breast cancer. This prospective, multicenter, phase II study evaluated 52 women with operable human epidermal growth factor receptor 2-negative breast cancer and axillary lymph node metastasis. Neoadjuvant DDCT (adriamycin plus cyclophosphamide or epirubicin plus cyclophosphamide followed by paclitaxel) was administrated every 2 weeks with G-CSF support. The study endpoints were the rates of pathological complete response (pCR), febrile neutropenia, treatment completion, toxicities, and the relative dose intensity (RDI). The pCR rate was 21.9% (9/41) and the triple-negative (TN) subtype was significantly associated with a high pCR rate (triple-negative: 53.3% vs. luminal A: 7.7% and luminal B: 0%; p = 0.003). The treatment completion rate was 80.8% (42/52) and the average RDI was 98.9%. Most adverse events were manageable and tolerable. Six patients (11.5%) developed febrile neutropenia. Grade 3–4 adverse events were slightly more common among older patients (57%) with a low protocol completion rate (≥ 65 years: 42.9% vs.

Background: Whether adjuvant chemotherapy is required for patients with intermediate-risk endocrine-responsive postmenopausal breast cancer remains unknown. The New primary Endocrine-therapy Origination Study (NEOS: N-SAS BC06 study: UMIN 000001090 (http://www.umin.ac.jp/) was a randomized controlled trial to verify the necessity of adjuvant chemotherapy in node-, ER+, and HER2- postmenopausal breast cancer patients who responded to neoadjuvant endocrine therapy. The primary registration and primary treatment have finished. This report evaluated clinical responses and radiological findings in the neoadjuvant LET treatment phase of 6 months. Methods: Patients meeting eligibility criteria received LET preoperatively in weeks 24-28 after primary enrollment. Patients evaluated as complete response (CR), partial response (PR) or stable disease (SD) by each investigators underwent secondary enrollment and will be divided at random into two arms, an arm given LET for 4.5-5 years after chemotherapy and another arm given only LET for 4.5-5 years. Patients evaluated as progressive disease during LET treatment will receive discretionary treatment. The primary endpoint was disease-free survival and secondary endpoints were overall survival, clinical response rate in neoadjuvant treatment phase, pathological response, breast-conserving surgery rate, DFS/OS in subgroups according to clinical response, safety, HRQOL, and cost-effectiveness. Results: Between May 2008 and June 2013, 905 patients entered primary registration. We excluded 42 patients without confirmed data. The 863 included patients’ characteristics at baseline are: median age: 63 years old, median Body Mass Index (BMI):23.90, T1c:37%, T2:63%, and PgR+:79%, and 74% of patients had planned breast-conserving surgery (BCS). The clinical responses were evaluated with calipers, ultrasound and MRI (or CT) at the baseline and end of treatment before surgery. Clinical response rates were 2, 48, 46 and 4% in CR, PR, SD and PD, respectively. Excluding those who could not enter secondary registration according to the protocol, 83 (56.1%) of 148 patients with planned total mastectomy were converted to BCS according to final radiological evaluations before surgery. The correlation between the tumor size on MRI (r=0.87) after neoadjuvant LET and the pathological invasive tumor size was stronger than with other modalities (r=0.68, 0.57, 0.33 by CT, US and calipers, respectively). On univariate analysis, a small tumor size (T1c rather than T2), PgR+, HER2:2+ and a high BMI at the baseline were significantly correlated with the clinical response. On multivariate analysis, PgR + (HR: 1.13, 95%CI: 1.01-1.27, p=0.032) and a small tumor size (HR: 1.11, 95%CI: 1.03-1.17, p=0.003) were significant independent predictors of the clinical response. Conclusion: This is the first clinical report of neoadjuvant hormone therapy for early breast cancer. Neoadjuvant LET therapy improved BCS rates. MRI was useful for predicting the residual pathological invasive tumor size. PgR + and a small tumor size at the baseline were significant independent predictors of the clinical response. Citation Format: Takehiko Sakai, Hiroji Iwata, Yoshie Hasegawa, Rikiya Nakamura, Hiromitsu Akabane, Shoichiro Ohtani, Masahiro Kashiwaba, Naruto Taira, Tatsuya Toyama, Yutaka Yamamoto, Tomomi Fujisawa, Norikazu Masuda, Takuhiro Yamaguchi, Hirofumi Mukai, Yasuo Ohashi. First report of clinicopathological analysis in neoadjuvant treatment phase in NEOS: A randomized study of adjuvant endocrine therapy with or without chemotherapy for postmenopausal breast cancer patients who responded to neoadjuvant letrozole [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-14-01.

Objective: To evaluate the effects of S-1, an orally administered 5-FU agent, versus taxane on patient-reported outcomes (PROs) in the SELECT BC trial. Methods: Patients with HER2-negative and endocrine treatment-resistant breast cancer with metastasis or recurrence after surgery were randomly assigned to receive first-line taxane or S-1. PROs (secondary endpoint) were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Patient Neurotoxicity Questionnaire (PNQ) at baseline and at 3, 6, and 12 months. We conducted a responder analysis for the QLQ-C30 and PNQ and created cumulative distribution function (CDF) plots as a sensitivity analysis. Results: The questionnaire response rates were over 80% from 386 patients, who completed at least one baseline questionnaire. S-1 was significantly superior to taxane with respect to 6 scales (physical functioning [p = 0.03], role functioning [p = 0.04], social functioning [p < 0.01], financial difficulties [p = 0.01], global health status [p = 0.02], and constipation [p < 0.01]) and sensory neuropathy (p = 0.01). The CDF plots partially supported the conclusions and their robustness. Conclusion: First-line S-1 therapy has clinical benefits with respect to many aspects of health-related quality of life for metastatic breast cancer patients.

Background Although there are a large number of epidemiological studies investigating the etiological role of lifestyle factors in breast cancer, there are few studies on the association between lifestyle factors and breast cancer prognosis. To investigate the influence of lifestyle factors such as diet and physical activity, use of complementary and alternative medicine, and psychosocial factors on prognosis, we designed a large-scale cohort study of female breast cancer patients in Japan. Methods The planned sample size is 7200. The cohort is being conducted in collaboration with several clinical trials, a cancer registry, and daily practice. Information on clinical factors, treatment, and follow-up will be obtained from the clinical trials and participating hospitals. A self-administered questionnaire is given to subjects before, immediately after, or 1 to 5 years after surgery. Blood and tissue samples are also collected. The primary endpoint is disease-free survival. The secondary endpoints are overall survival and health-related quality of life. The follow-up period will be at least 5 years after the last participant is enrolled. Recruitment began in November 2007. Current status As of April 2017, there are 5852 patients enrolled in the study along with 1430 biological samples and the study is still ongoing. The number of subjects enrolled in the study is already the largest in the world. Conclusions The ROK study will provide much important evidence for breast cancer survivorship.

Trials of adjuvant endocrine therapy for breast cancer have shown that aromatase inhibitors have little impact on global health-related quality of life (HRQoL), but have significant effects on patient-reported endocrine symptoms (ESs). There are few studies of HRQoL and psychological distress during preoperative endocrine therapy performed to determine endocrine responsiveness. The NEOS trial is a multicenter, phase 3 randomized controlled trial in postmenopausal women with hormone receptor-positive breast cancer. The primary aim of the trial was to evaluate the need for adjuvant chemotherapy in patients with clinical T1c-T2N0M0, hormone receptor-positive tumors who responded to neoadjuvant letrozole (LET) administered for 24-28 weeks before surgery. The primary endpoint was disease-free survival and the secondary endpoints included adverse events, HRQoL, and cost-effectiveness. In a HRQoL sub-study, subjects were assessed at baseline and 4 and 16 weeks after starting neoadjuvant LET, using the functional assessment of cancer therapy-breast and its ES subscale, and the hospital anxiety and depression scale. HRQoL and psychosocial distress were analyzed in the uncontrolled phase during 24-28 weeks of neoadjuvant LET therapy in the NEOS trial. From May 16, 2008, to December 14, 2011, 503 patients were recruited into the HRQoL sub-study. The full analysis set included 497 patients with a mean age of 63-years old. The questionnaire response rates at enrollment and 4 and 16 weeks were 94.4, 90.7, and 89.1 %, respectively. There were no significant changes in the FACT-G or B-trial outcome index over time, but the social and family well-being score and the ES subscale deteriorated significantly, and the number of patients with clinically significant hot flush increased significantly. Anxiety, depression, and emotional well-being improved significantly after neoadjuvant LET. Neoadjuvant endocrine therapy with LET had no impact on global HRQoL, but did influence endocrine-related symptoms such as hot flush. This study is registered as UMIN000001090.

Introduction: The one-step nucleic acid amplification (OSNA) assay is a new method to detect sentinel lymph node (SLN) metastases using cytokeratin 19 (CK19) mRNA in early breast cancer. Here we retrospectively analyzed the advantages and disadvantages of the OSNA assay. Methods: In a trial period, SLNs were divided into two sections, and we examined one side using the OSNA assay. The other side was examined by pathologists. After this period, we examined whole SLNs using only the OSNA assay. The patients with positive nodes by OSNA assay and/or pathology required axillary dissection. Results: We examined 27 primary breast cancer patients (36 SLNs) during the trial period. The overall concordance rate between the OSNA assay and pathology results was 91%. In the later period, 157 patients (217 SLNs) were examined. The CK19-positive rate obtained by the OSNA assay was 16.5% (macrometastases OSNA (++) : 7.2%, micrometastases OSNA (+) : 9.2%). The non-SLN positive rate among the CK19-positivecases was 23%. The OSNA assay's false negative was one case in which the expression of CK-19 on the primary tumor and lymph node was not detected. Conclusions: Our OSNA assay results were comparable to those obtained using a conventional pathological technique. Pathologists and laboratory technicians could save time and effort by using the OSNA assay when seeking the precise diagnosis during surgery.

Background Aim: To clarify the clinicopathological characters and treatments and prognosis in elderly breast cancer patients using the Japanese Breast Cancer Registry (JBCR) system. Methods We reviewed data from JBCR, which is the nation-wide registry of newly diagnosed and operated primary breast cancer patients in Japan. To clarify its characteristics, we compared elderly patients aged 75 and over (elderly) with aged from 65 to 74 (young-old; y-o) and that from 55 to 64 (post-menopausal; p-m), respectively. Results In total 132,240 cases diagnosed between 2004 and 2011 were reviewed (elderly; n = 27,385, y-o; n = 43,839, p-m; n = 61,016). In histology, the proportion of mucinous carcinoma and apocrine carcinoma were higher in elderly (6.1%, 1.8%, y-o; 3.5%, 1.7%, p-m; 1.8%, 1.3%, respectively). Patients with clinical stage II and III were more frequent in elderly (45.1%, y-o; 39.0%, p-m; 39.8%). ER -positive rate was higher (76.8%, y-o; 76.3%, p-m; 72.7%) and HER2-positive rate was lower in elderly (10.5%, y-o; 12.8%, p-m; 18.6%, p Table . 238P Age ≧75 65-74 55-64 Distant disease-free survival (%) 93.1 94.3 93.1 Overall survival (%) 84.3 93.7 94.4 Breast cancer-specific survival (BCSS) (%) 94.2 96.7 95.9 Other disease death (%) 48.0 35.8 20.6 Conclusions Elderly patients suffered from more advanced disease at the time of diagnosis. Irradiation after BCS and primary systemic chemotherapy was more frequently omitted in the elderly patients. Overall, BCSS was similar among ages, but the rate of other causes of death was higher in elderly patients. Legal entity responsible for the study The authors. Funding Japanese Breast Cancer Society. Disclosure All authors have declared no conflicts of interest.

1070 Background: Although nab-paclitaxel (nab-PTX) has shown superior efficacy compared to conventional paclitaxel in metastatic breast cancer (MBC), chemotherapy induced peripheral neuropathy (CIPN) was more frequently observed in nab-PTX. In a single arm Phase 2 trail (CA002-0LD), low dose nab-PTX (175mg/m2) every 3 weeks (q3w) demonstrated a good objective response rate (39.5%) without grade 3 or higher CIPN. Herein, we conducted multicenter randomized controlled study to evaluate optimal dose of nab-PTX comparing lower dose (LD or MD) to standard dose (SD). Methods: This study compared three different doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2) in patients with HER2 negative metastatic breast cancer. Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses are estimated by the logistic regression. Optimal dose was selected by 2 step selection. At first, if hazard ratio (HR) for PFS was less than 0.75 or more than 1.33, the inferior dose was dropped. Then, if estimated incidence rate of grade 3/4 neurotoxicity exceed10%, that dose was also dropped. This trial is registered with the University Hospital Medical Information Network (UMIN), Japan (protocol ID C000012429). Results: In this study, 141 patients were randomly assigned to SD (n = 47), MD (n = 46) or LD (n = 48). Median PFS was 6.66 vs 7.34 vs 6.82 months, respectively. HR was 0.73 (95% confidence interval (CI): 0.42-1.28) in MD vs SD. SD was dropped due to inferiority to MD. HR was 0.77 (95%CI 0.47-1.28) in LD vs SD, and 0.96 (95%CI 0.56-1.66) in LD vs MD. LD and MD were carried over to next step due to equivalence. Overall survival was not different among all dose arms. Rate of dose reduction by treatment course was significantly higher in SD arm. Estimated incidence of grade 3/4 neurotoxicity rate was 29.5% in SD, 14.0% in MD and 5.9% in LD. Final selected dose was LD 180mg/m2. HR-QOL results will be presented. Conclusions: Low dose nab-PTX at 180 mg/m2/3 weeks could be an optimal dose with good clinical efficacy and tolerability for patients with MBC. Clinical trial information: C000012429.

e14182 Background: Metformin is one of the most commonly prescribed drugs for type 2 diabetes, and some reports have suggested that metformin may reduce cancer risk. Diabetics treated with metformin have a 23% reduction in the risk of cancer, including breast cancer. In addition, it is reported that the breast cancer patients with metformin treatment for diabetes showed favorable prognosis compared with those without metformin treatment. However, the mechanism underlying the positive effects of metformin on cancer treatment remains unclear. Methods: We conducted a prospective study to evaluate the effect of preoperative metformin on early breast cancer patients. The patients took a daily dose of metformin orally for 7 to 21 days before surgery. We evaluated the effects on immunological factors (TILs, CD4+, CD8+, PD-L1 and ALDH1) by comparing core needle biopsies (CNB) obtained before surgery with surgical specimens. Results: Seventeen breast cancer patients were enrolled in this prospective study and administered metformin before surgery, during the period from January to December 2016. We analyzed 59 patients who received surgery during the same period as a control group. In the control group, there was no significant difference in TILs between CNB and surgical specimens (Rs = 0.63). In the metformin group, TILs were negative in CNB and surgical specimens of 15 (88%) and 8 (48%) cases, low in 2 (12%) and 8 (48%), and intermediate in 0 and 1 (6%), respectively. These TILs increases were confirmed in 5 (29%) patients (p = 0.09), while a decrease was confirmed in 2 (12%). The expressions of CD4+ and CD8+ by TILs were increased in 41% and 18% of surgical specimens, respectively. (p = 0.02, p = 0.09) However, there was no statistically significant difference in these immunological factors and PD-L1 or ALDH1 expression between before and after metformin. Conclusions: In our small cohort, preoperative metformin administration shows positive impact on CD4 positive lymphocytes significantly and has tendency of increasing both TILs and CD8 positive lymphocytes. However, we should keep in mind that our sample size is small. Further study is necessary to uncover the mechanisms of favorable effects of metformin on breast cancer patients.